title: Acquired resistance to anti-VEGF therapy in glioblastoma is associated with a mesenchymal transition.
abstract: OBJECTIVE
  Antiangiogenic therapy reduces vascular permeability and delays progression but may ultimately promote an aggressive treatment-resistant phenotype. The aim of the present study was to identify mechanisms responsible for glioblastoma resistance to antiangiogenic therapy.
  
  
  METHODS
  Glioma stem cell (GSC) NSC11 and U87 cell lines with acquired resistance to bevacizumab were developed from orthotopic xenografts in nude mice treated with bevacizumab. Genome-wide analyses were used to identify changes in tumor subtype and specific factors associated with resistance.
  
  
  RESULTS
  Mice with established parental NSC11 and U87 cells responded to bevacizumab, whereas glioma cell lines derived at the time of acquired resistance to anti-VEGF therapy were resistant to bevacizumab and did not have prolongation of survival compared with untreated controls. Gene expression profiling comparing anti-VEGF therapy-resistant cell lines to untreated controls showed an increase in genes associated with a mesenchymal origin, cellular migration/invasion, and inflammation. Gene-set enrichment analysis showed that bevacizumab-treated tumors showed a highly significant correlation to published mesenchymal gene signatures. Mice bearing resistant tumors showed significantly greater infiltration of myeloid cells in NSC11- and U87-resistant tumors. Invasion-related genes were also upregulated in both NSC11 and U87 resistant cells which had higher invasion rates in vitro compared with their respective parental cell lines.
  
  
  CONCLUSIONS
  Our studies identify multiple proinflammatory factors associated with resistance and identify a proneural to mesenchymal transition in tumors resistant to antiangiogenic therapy.
authors.affiliation: Brain Tumor Center, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Piao
authors.forename: Ji
authors.initials: J
authors.lastname: Liang
authors.forename: Lindsay
authors.initials: L
authors.lastname: Holmes
authors.forename: Verlene
authors.initials: V
authors.lastname: Henry
authors.forename: Erik
authors.initials: E
authors.lastname: Sulman
authors.forename: John F
authors.initials: JF
authors.lastname: de Groot
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D006801:Humans; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab